The single most important cause of corneal blindness is herpes simplex virus (HSV) type 1 with as many as 500,000 cases per year in the US. This is a result of HSV's ability to establish latent infections that can reactivate to cause recurrent herpetic kerititis. The rate of recurrence in the eye has a major impact on the degree of corneal damage and the eventual outcome for the patient. Because the number of neurons in which latency is established directly correlates with the frequency of HSV reactivation, the factors that influence the establishment of latency also dictate the outcome of ocular infections. Although a general descriptive understanding of HSV establishment of latency is well established, most of the molecular details await discovery. A central question is how expression of the lytic viral gene cascade is repressed in a very large pool of neurons at the site of latency. The latently associated transcript locus (LAT) is the only viral gene known to specifically regulate the establishment of latency without exerting any impact on viral replication. The expression of LAT prevents the death of thousands of sensory neurons, and increases the number of neurons in which latency is established by 400%. How LAT accomplishes these tasks is controversial and presently not known. Defining how LAT preserves neurons and promotes the establishment of latency will provide insights into the viral/host cell interface critical to regulating this process, and point to antiviral targets potentially useful in preventing and/or controlling viral reactivation. Preventing reactivation would reduce the spread of infection through the population and also reduce the reactivation-mediated repetitive tissue insult responsible for corneal blindness. Our long-term goal is to delineate the molecular mechanisms of HSV pathogenesis in vivo, in order that effective therapeutic strategies can be developed to treat and/or prevent infection. Our objective will be to determine the molecular mechanism(s) by which LAT prevents the death of neurons and promotes the establishment of latency. Our central hypothesis is that LAT functions as a selective "Off Switch" in neurons, inhibiting lytic gene expression during the establishment, maintenance, and reactivation stages of infection. Specifically we will (1) Determine how the LAT gene prevents neuronal death and promotes the establishment of latent infections; (2) Determine the role of the LAT gene in the establishment of latency and/or reactivation from latency in the rabbit ocular model; (3) Determine the biochemical mechanisms whereby the LAT gene exerts its biologically important effects.